(1S,3R,4R)-2-Azanorbornylmethanol, an Efficient Ligand for Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Ketones

Full text of DOI:10.1021/jo972082o

J . Org. Chem. 1998, 63, 2749-2751
2749
Sch em e 1a
(1S,3R,4R)-2-Aza n or bor n ylm eth a n ol, a n
Efficien t Liga n d for Ru th en iu m -Ca ta lyzed
Asym m etr ic Tr a n sfer Hyd r ogen a tion of
Keton es
Diego A. Alonso, David Guijarro, Pedro Pinho,
Oliver Temme, and Pher G. Andersson*
a
Reagents and conditions: (i) 0.25 mol % [RuCl2(HMB)]2, 2 mol
% L* (1-3), 2.5 mol % i-PrOK, i-PrOH.
Department of Organic Chemistry, Uppsala University,
Box 531, S-751 21 Uppsala, Sweden
Ta ble 1. Hyd r ogen -Tr a n sfer Red u ction of Acetop h en on e
Received November 13, 1997
Usin g Liga n d s 1-3
Ruthenium-catalyzed hydrogen transfer from 2-pro-
panol to ketones is an efficient method for the prepara-
tion of secondary alcohols.1 In contrast to hydrogenation
using molecular hydrogen, the transfer hydrogenation of
ketones is carried out in a very simple way and does not
require the use of reactive metal hydrides or hydrogen.
As a consequence, much effort has been put into the
development of asymmetric versions of the reaction.
Very recently, Noyori developed an efficient and highly
enantioselective catalyst using diamines as chiral ligands
to ruthenium.2 Other types of chiral phosphorus and/or
nitrogen ligands have also been used, however, with
rather varying levels of yields and selectivity.3
Despite the progress recently being made on this
catalytic enantioselective process, there are only a few
examples that use simple amino alcohols as chiral ligands
for asymmetric transfer hydrogenation of ketones.4 We
have recently reported the use of 2-azanorbornyl deriva-
tives as ligands in asymmetric catalysis.5 The promising
results obtained prompted us to apply some of these rigid
proline analogues to the catalytic hydrogen-transfer
process.6 Herein we present our preliminary results for
this reaction.
a
b
Determined by GLC and 300 MHz 1H NMR analysis. De-
termined by HPLC analysis (ChiralCel OD-H; 5% of i-PrOH in
hexane; 0.5 mL/min). c Determined from the sign of rotation of the
d
isolated product. The reaction was run at 83 °C.
To study the effect of the ligand backbone, (S)-2-
pyrrolidinemethanol (1) was compared with the confor-
mationally constrained (1S,3R,4R)-3-(hydroxymethyl)-2-
azabicyclo[2.2.1]heptane (2) and (1S,3R,4R)-3-(2-hydroxy-
2-propyl)-2-azabicyclo[2.2.1]heptane (3) in the reduction
of acetophenone 4a (Scheme 1). In a typical experiment,
a solution of the ketone (1 equiv, 0.1 M in dry 2-propanol),
the ruthenium complex ([RuCl2(HMB)]2;7 0.25 mol %), the
chiral amino alcohol (2 mol %), and i-PrOK (2.5 mol %)
was stirred under argon at room temperature for 5-16
h in dry i-PrOH. The use of 1 gave rise to a rather slow
and unselective reaction for reasons not yet fully under-
stood (16% conversion and 8% ee over the unexpected
enantiomer, after 6.5 h; entry 1, Table 1). However,
amino alcohol 2 gave an excellent result (92% conversion
and 95% ee after 5 h; entry 2, Table 1). In the presence
of the sterically more hindered ligand 3 no reaction was
observed at room temperature. For some hindered
systems, it has been observed that the reactions may be
carried out at higher temperatures without significant
loss of enantioselectivity.3m In the case of ligand 3,
however, carrying the reaction out at reflux led to the
formation of racemic product (entry 3, Table 1). It
therefore seems that 2-azanorbornyl carbinols with ter-
tiary alcohol moieties are not useful in this catalytic
system.
(1) (a) Sasson, Y.; Blum, J . Tetrahedron Lett. 1971, 24, 2167. (b)
Sasson, Y.; Blum, J . J . Org. Chem. 1975, 40, 1887. (c) Linn, D. E.;
Halpern, G. J . Am. Chem. Soc. 1987, 109, 2969. (d) Noyori, R.; Takaya,
H. Acc. Chem. Res. 1990, 23, 345. (e) Chowdhury, R. L.; Ba¨ckvall, J .
E. J . Chem. Soc., Chem. Commun. 1991, 1063.
(2) (a) Hashiguchi, S.; Fujii, A.; Takehara, J .; Ikariya, T.; Noyori,
R. J . Am. Chem. Soc. 1995, 117, 7562. (b) Fujii, A.; Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J . Am. Chem. Soc. 1996, 118, 2521.
(c) Haack, K. J .; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 285. (d) Matsumura, K.; Hashiguchi,
S.; Ikariya, T.; Noyori, R. J . Am. Chem. Soc. 1997, 119, 8738.
(3) (a) For a review see: Zassinovich, G.; Mestroni, G.; Gladiali, S.
Chem. Rev. 1992, 92, 1051. (b) Gladiali, S.; Pinna, L.; Delogu, G.; De
Martin, S.; Zassinovich, G.; Mestroni, G. Tetrahedron: Asymmetry
1990, 1, 635. (c) Muller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. Helv.
Chim. Acta 1991, 74, 232. (d) Genet, J .-P.; Ratovelomonana-Vidal, V.;
Pinel, C. Synlett 1993, 34, 478. (e) Krasik, P.; Alper, H. Tetrahedron
1994, 50, 4347. (f) Yang, H.; Alvarez, M.; Lugan, N.; Mathieu, R. J .
Chem. Soc., Chem. Commun. 1995, 1721. (g) Langer, T.; Helmchen,
G. Tetrahedron Lett. 1996, 37, 1381. (h) Langer, T.; J anssen, J .;
Helmchen, G. Tetrahedron: Asymmetry 1996, 7, 1599. (i) J iang, Q.;
Van Plew, D.; Mutuza, S.; Zhang, X. Tetrahedron Lett. 1996, 37, 797.
(j) Puntener, K.; Schwink, L.; Knochel, P. Tetrahedron Lett. 1996, 37,
8165. (k) Gamez, P.; Dunjic, B.; Lemaire, M. J . Org. Chem. 1996, 61,
5196. (l) J iang, Y.; J iang, Q.; Zhu, G.; Zhang, X. Tetrahedron Lett. 1997,
38, 215. (m) Sammakia, T.; Stangeland, E. L. J . Org. Chem. 1997, 62,
6104.
The bicyclic ligand structure is particularly attractive
as it is easily prepared in either enantiomeric forms and
on a multigram scale with the use of only inexpensive
(4) (a) Takehara, J .; Hashiguchi, S.; Fujii, A.; Invoe, S.-I.; Ikariya,
T.; Noyori, R. J . Chem. Soc., Chem. Commun. 1996, 233. (b) Noyori,
R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
(5) So¨dergren, M. J .; Andersson, P. G. Tetrahedron Lett. 1996, 37,
7577.
(6) During the progress of this work, Wills et al. reported on the
use of conformationally rigid 2-indanol derivatives as chiral ligands
for the asymmetric transfer hydrogenation of ketones; see: Palmer,
M.; Walsgrove, T.; Wills, M. J . Org. Chem. 1997, 62, 5226.
(7) HMB ) hexamethylbenzene. For the synthesis of the Ru
complexes see: (a) Bennett, M. A.; Smith, A. K. J . Chem. Soc., Dalton
Trans. 1974, 233. (b) Bennett, M. A.; Matheson, T. W.; Robertson, G.
B.; Smith, A. K.; Tucker, P. A. Inorg. Chem. 1980, 19, 1014.
S0022-3263(97)02082-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/21/1998

2750 J . Org. Chem., Vol. 63, No. 8, 1998
Notes
Sch em e 2a
Ta ble 2. Hyd r ogen Tr a n sfer Red u ction of Keton es 4a -g
Usin g Liga n d 2a
product
[RuCl2- time
entry ketone (arene)]2 (h) no.
yieldb
(%)
eec
(%) confignd
1
2
3
4
5
6
7
8
9
10
11
12
13
4a
4b
4c
4d
4e
4f
4g
4a
4b
4c
4d
4e
4f
HMB
HMB
HMB
HMB
HMB
HMB
HMB
p-cymene 1.5 5a
p-cymene 1.5 5b
p-cymene 1.5 5c
p-cymene 1.5 5d
p-cymene 1.5 5e
p-cymene 1.5 5f
5
3
5
5
5
5
5
5a
92
95
Se
Se
Se
Se
Sg
Sh
5b 100 (98)f 94
5c
5d
5e
5f
81
81
70
17
i
91
92
81
60
78
53
83
90
89
83
j
94
97
93
92
95
95
5g
S
S
S
S
Sg
Sh
a
General procedure for the hydrogen-transfer reduction: The
ruthenium complex dimer (10 µmol) and 2 (80 µmol) were weighed
into a round-bottom flask, and any moisture was azeotropically
removed via evaporation of benzene (5 × 5 mL) at reduced
pressure. A condenser was attached, and the residue was dissolved
in dry i-PrOH (5 mL). The solution was refluxed under argon for
30 min before it was cooled to rt and transferred to a flask
containing a solution of the ketone (4 mmol) and potassium
isopropoxide (100 µmol) in i-PrOH (35 mL). The resulting solution
was then stirred for the time indicated at rt under argon
(monitored by GC and/or 1H NMR), neutralized with 1 M solution
of HCl, and concentrated in vacuo to give the crude product, which
was purified by flash column chromatography (SiO2, EtOAc/
a
Reagents and conditions: (i) H2 (150 psi), 5% Pd-C, EtOH,
98%, 97% ee;12 (ii) LiAlH4, THF, 90%; (iii) PhCH2Br, K2CO3,
CH3CN, 78%; (iv) MeMgBr, THF, 84%; (v) H2 (150 psi), 5% Pd-
C, EtOH, 98%.
reagents (Scheme 2). Adduct 6 is prepared in high yield
via a highly exo and diastereoselective aza-Diels-Alder
reaction employing either (+)- or (-)-phenylethylamine
as the source of chirality.8 Hydrogenation/hydrogenoly-
sis9 and subsequent reduction with LiAlH4 affords amino
alcohol 2 in 92% overall yield from 6.
Next, we wanted to investigate whether the very
promising results obtained with 2 could be extended to
other substrates, and indeed, it was found that a variety
of prochiral ketones could be reduced with high enanti-
oselectivity (Table 2, Scheme 3). In accordance with
Noyori’s observations,4a ketones with a bulky substituent
adjacent to the carbonyl reacted very slowly under the
reaction conditions (entry 7, Table 2).
b
pentane 90/10). Yield was determined by GLC and 300 MHz 1H
NMR analysis. c Determined by HPLC analysis (ChiralCel OD-
d
H; 5% of i-PrOH in hexane; 0.5 mL/min). Determined from the
sign of rotation of the isolated product. e Commercially available
compounds. f Isolated yield after flash chromatography (silica gel,
g
h
i
pentane/EtOAc 90/10). See ref 10. See ref 11. Less than 5%
j
of conversion was obtained after 5 h. Not determined.
Sch em e 3a
Finally, we also studied the influence of the arene
ligand in the ruthenium complex. It was found that the
use of [RuCl2(p-cymene)]2 instead of [RuCl2(hexamethyl-
benzene)]2 resulted in a higher rate and improved
selectivity for all the substrates studied (compare entries
1-6 with 8-13, Table 2). Using this complex, the
secondary alcohols were obtained with ee’s ranging from
92 to 97%.
In conclusion, we have demonstrated that ruthenium
complexes having 2-azanorbornylmethanol as chiral ligand
are efficient catalysts for the enantioselective transfer
hydrogenation of aromatic ketones, affording the corre-
sponding secondary alcohols in excellent ee’s. Studies
are in progress in order to further improve the enanti-
oselectivity and also to rationalize the origin of the
asymmetric induction observed with this new catalytic
system.
a
Reagents and conditions: (i) 0.25 mol % [RuCl2(arene)]2, 2 mol
% 2 (97% ee12), 2.5 mol % i-PrOK, i-PrOH.
that it was treated with 5% Et3N in pentane and the column
was eluted with the same solvent mixture until the coming
eluent was basic according to pH paper. TLC’s were prefomed
on precoated plates, SIL G-60 UV254, purchased from Macherey-
Nagel. When mentioned, deactivated silica gel means that the
TLC plate was eluted with 5% Et3N in pentane and dried before
applying the sample. HPLC analyses were carried out using a
chiral column (ChiralCelOD-H), a 254 nm UV detector, and a
flow rate of 0.5 mL/min.
Exp er im en ta l Section
For general experimental information see ref 13.
Flash chromatography was preformed on silica gel (Matrex
60A, 37-70 µm). When mentioned, deactivated silica gel means
(8) (a) Stella, L.; Abraham, M.; Feneau-Dupont, J .; Tinant, B.;
Declercq, J . P. Tetrahedron Lett. 1990, 18, 2603. (b) Waldmann, H.;
Braun, M. Liebigs Ann. Chem. 1991, 1045.
(9) Nakano, H.; Kumagai, N.; Matsuzaki, H.; Kabuto, C.; Hongo,
H. Tetrahedron: Asymmetry 1997, 9, 1391.
(10) Watanabe, M.; Araki, S.; Butsugan, Y. J . Org. Chem. 1991, 56,
2218.
Eth yl (1S,3R,4R)-2-[[(S)-1-P h en yleth yl]a m in o]-2-a za bi-
cyclo[2.2.1]h ep t-5-en e-3-ca r boxyla te (6). Compound 6 was
prepared via an aza-Diels-Alder reaction between cyclopenta-
(11) Mori, K.; Bernotas, R. Tetrahedron: Asymmetry 1990, 1, 87.
(12) Determined by HPLC analysis of the N-benzoyl derivative of
ethyl (1S,3R,4R)-2-azabicyclo[2.2.1]heptane-3-carboxylate (7).
(13) Bedekar, A. V.; Koroleva, E. B.; Andersson, P. G. J . Org. Chem.
1997, 62, 2518.

Notes
J . Org. Chem., Vol. 63, No. 8, 1998 2751
diene, an iminium ion derived from ethyl glyoxylate and (S)-1-
phenylethylamine, following a literature procedure.14 Purifica-
tion by flash chromatography (deactivated silica gel, pentane/
Et2O 95/5-80/20) afforded pure compound 6 (60% yield). All
the physical and spectroscopic data for compound 6 were in
complete agreement with the reported data for its enantiomer,14
except for the sign of the optical rotation.
) 9.4, 1.4 Hz), 1.30-1.44, 1.61-1.71, 1.92-2.05 (2, 1 and 2 H,
respectively, 3 m), 2.50-2.54 (1 H, m), 2.67 (1 H, s), 3.31-3.33
(1 H, m), 3.72, 3.76 (2H, 2 d, J ) 12.9 Hz), 4.00 (2 H, q, J ) 7.1
Hz), 7.18-7.37 (5 H, m); 13C NMR δ 14.2, 22.4, 29.3, 36.6, 42.4,
55.5, 59.6, 60.2, 69.9, 126.8, 128.1, 129.0, 139.4, 173.5; MS (EI)
m/z (rel intensity) 259 (M+, <1), 186 (39), 158 (32), 91 (100), 65
(21). Anal. Calcd for C16H21NO2: C, 74.10; H, 8.16; N, 5.40.
Found: C, 73.89; H, 8.17; N, 5.37.
(1S,3R,4R)-2-Ben zyl-3-(2-h ydr oxy-2-pr opyl)-2-azabicyclo-
[2.2.1]h ep ta n e (9). To a solution of ethyl (1S,3R,4R)-2-benzyl-
2-azabicyclo[2.2.1]heptane-3-carboxylate (1.5 mmol) in dry THF
at -30 °C was added dropwise a 3 M solution of MeMgBr (3.75
mmol) in dry Et2O (4 mL). The reaction was stirred for 7 h,
allowing the temperature to rise to room temperature. Then,
the reaction mixture was hydrolyzed with water and extracted
with ethyl acetate (3 × 20 mL). The organic layer was dried
over MgSO4 and evaporated and the residue purified by flash
chromatography (pentane/acetone 95/5) to afford 311 mg (84%
Eth yl (1S,3R,4R)-2-Aza bicyclo[2.2.1]h ep ta n e-3-ca r boxy-
la te (7). A solution of the Diels-Alder adduct 6 (7.87 g, 29.0
mmol) in absolute ethanol (50 mL) was stirred under a hydrogen
pressure of 100 psi at room temperature for 48 h in the presence
of 5% Pd-C (1.57 g, 20 wt %). The Pd-C was removed by
filtration through Celite and evaporation of the solvent yielded
4.81 g (98% yield) of the pure NH amino ester: Rf 0.53 (pentane/
acetone 1/1; deactivated silica gel); [R]24 ) -28.2 (c ) 1.26,
D
CHCl3); IR (neat, cm-1) 3310, 1728, 1206; 1H NMR δ 1.21 (1 H,
br d, J ) 9.8 Hz), 1.25 (3 H, t, J ) 7.1 Hz), 1.34-1.66 (5 H, m),
2.18 (1 H, br s), 2.59, 3.27, 3.50 (1 H each, 3 br s), 4.15 (2 H, q,
J ) 7.1 Hz); 13C NMR δ 14.2, 28.4, 31.1, 35.7, 41.7, 56.2, 61.0,
63.6, 174.5; MS (EI) m/z (rel intensity) 169 (M+, 8), 131 (26), 73
yield) of pure product: mp ) 48-50 °C; Rf 0.40 (pentane/acetone
1
4/1); [R]25 ) +31.5 (c ) 1.09, CHCl3); IR (KBr, cm-1) 3482; H
D
(23), 69 (100), 57 (25), 55 (40). Anal. Calcd for C9H15
-
NMR δ 1.07 (1 H, br d, J ) 9.5 Hz), 1.21, 1.23 (3 H each, 2 s),
1.19-1.30, 1.57-1.66, 1.83-1.89, 2.01-2.09 (2, 1, 1 and 1 H,
respectively, 4 m), 2.01 (1 H, s), 2.38-2.42 (1 H, m), 3.12 (1 H,
br s), 3.18 (1 H, br s), 3.70, 4.02 (2H, 2 d, J ) 14.0 Hz), 7.22-
7.38 (5 H, m); 13C NMR δ 22.1, 26.5, 29.8, 30.3, 36.0, 39.5, 55.5,
58.0, 71.2, 76.3, 126.8, 128.3 (4 C), 140.0; MS (EI) m/z (rel
intensity) 230 (M+ - 15, 2), 186 (56), 158 (45), 91 (100), 65 (18).
Anal. Calcd for C16H23NO: C, 78.32; H, 9.45; N, 5.71. Found:
C, 78.34; H, 9.42; N, 5.69.
NO2‚0.1H2O: C, 63.21; H, 8.96; N, 8.19. Found: C, 62.98; H,
9.06; N, 8.11.
(1S ,3R ,4R )-3-(H y d r o x y m e t h y l)-2-a za b ic y c lo [2.2.1]-
h ep ta n e (2). A solution of ethyl (1S,3R,4R)-2-azabicyclo[2.2.1]-
heptane-3-carboxylate (2.60 g, 15.4 mmol) in dry THF (20 mL)
was added to a suspension of LiAlH4 (1.17 g, 30.8 mmol) in dry
THF (20 mL) at 0 °C under argon. After completion according
to TLC, the reaction was quenched by adding consecutively 1.2
mL of water, 1.2 mL of 5% NaOH solution, and 3.6 mL of water.
The mixture was then stirred for 30 min at room temperature.
Filtration and solvent evaporation afforded 1.77 g of pure
compound 2 as a white solid (90% yield) that was recrystallized
from hexane: mp ) 43-45 °C; Rf 0.22 (methanol; deactivated
(1S,3R,4R)-3-(2-H yd r oxy-2-p r op yl)-2-a za b icyclo[2.2.1]-
h ep ta n e (3). A solution of (1S,3R,4R)-2-benzyl-3-(2-hydroxy-
2-propyl)-2-azabicyclo[2.2.1]heptane (259 mg, 1.05 mmol) in
absolute ethanol (25 mL) was submitted to hydrogenolysis in
the presence of 5% Pd-C (51 mg, 20 wt %) under a hydrogen
pressure of 150 psi at room temperature for 24 h. The Pd-C
was removed by filtration through Celite, and evaporation of
the solvent afforded 160 mg of the desired product (98% yield)
as a low-melting-point white solid that was recrystallized from
silica gel); [R]25.6 ) -62.9 (c ) 1.03, CHCl3); IR (neat, cm-1
)
D
3383; 1H NMR δ 1.15 (1 H, dt, J ) 9.8, 1.4 Hz), 1.40-1.30 (2 H,
m), 1.72-1.53 (3 H, m), 2.17 (1 H, m), 2.89-2.79 (3 H, m), 3.17
(1 H, dd, J ) 10.7, 8.2 Hz), 3.40 (1 H, dd, J ) 10.7, 5.4 Hz), 3.43
(1 H, br s); 13C NMR δ 28.8, 32.9, 34.7, 38.8, 55.8, 62.2, 65.3;
MS (EI) m/z (rel intensity) 127 (M+, 2), 96 (49), 68 (100). Anal.
Calcd for C7H13NO: C, 66.11; H, 10.30; N, 11.01. Found: C,
65.18; H, 10.37; N, 10.85.
pentane/ether: Rf 0.24 (pentane/ether 1/1); [R]24.2 ) -37.3 (c
D
) 0.71, CHCl3); IR (KBr, cm-1) 3284, 3176; 1H NMR δ 1.02-
1.40 (9 H, m with 2 s at 1.05 and 1.15), 1.42-1.76 (3 H, m), 2.39
(1 H, br s), 2.47 (1 H, s), 2.90 (1 H, br s), 3.46 (1 H, br s); 13C
NMR δ 25.3, 28.7, 30.1, 32.4, 34.8, 37.7, 55.4, 68.8, 70.4; MS
(EI) m/z (rel intensity) 140 (M+ - 15, 2), 96 (18), 68 (100), 67
(41), 59 (34).
Eth yl (1S,3R,4R)-2-Ben zyl-2-a za bicyclo[2.2.1]h ep ta n e-3-
ca r boxyla te (8). Anhydrous K2CO3 (335 mg, 2.4 mmol) was
added to a solution of ethyl (1S,3R,4R)-2-azabicyclo[2.2.1]-
heptane-3-carboxylate (339 mg, 2.0 mmol) and benzyl bromide
(0.29 mL, 2.4 mmol) in CH3CN (10 mL) at room temperature,
and the reaction mixture was stirred for 32 h. The solvent was
then evaporated, water was added, and the resultant mixture
was extracted with ethyl acetate (3 × 20 mL). The combined
organic layers were washed with brine, dried over MgSO4, and
evaporated and the residue purified by flash chromatography
(pentane/Et2O 99/1 to 95/5) to afford 407 mg (78% yield) of the
Ack n ow led gm en t. We thank the Swedish Natural
Research Council, The Swedish Foundation for Strategic
Research, Astra Arcus, and Pharmacia & UpJ ohn for
generous financial support. D.G. and D.A.A. are also
grateful to the Wenner-Gren Foundation for grants.
pure benzyl ester: Rf 0.53 (pentane/Et2O 1/1); [R]25 ) -0.9 (c
D
Su p p or tin g In for m a tion Ava ila ble: HPLC traces for
compounds 5a -f (12 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
) 1.06, CHCl3), [R]25365 ) -8.1 (c ) 1.06, CHCl3); IR (neat, cm-1
)
1742, 1155; 1H NMR δ 1.13 (3 H, t, J ) 7.1 Hz), 1.24 (1 H, dt, J
(14) (a) Stella, L.; Abraham, M.; Feneau-Dupont, J .; Tinant, B.;
Declercq, J . P. Tetrahedron Lett. 1990, 18, 2603. (b) Waldmann, H.;
Braun, M. Liebigs Ann. Chem. 1991, 1045.
J O972082O